Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation.
Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation.
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DOI：
10.1056/nejmoa0909825
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发表时间：
2010-11-18
期刊：
影响因子：
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通讯作者：
Ramsey BW
中科院分区：
文献类型：
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作者：
Accurso FJ;Rowe SM;Clancy JP;Boyle MP;Dunitz JM;Durie PR;Sagel SD;Hornick DB;Konstan MW;Donaldson SH;Moss RB;Pilewski JM;Rubenstein RC;Uluer AZ;Aitken ML;Freedman SD;Rose LM;Mayer-Hamblett N;Dong Q;Zha J;Stone AJ;Olson ER;Ordoñez CL;Campbell PW;Ashlock MA;Ramsey BW
囊性纤维化治疗的一种新方法涉及改善突变的囊性纤维化跨膜传导调节因子（CFTR）的功能。VX - 770是一种CFTR增效剂，已被证明在体外可增加野生型和有缺陷的细胞表面CFTR的活性。
我们将39名患有囊性纤维化且至少有一个G551D - CFTR等位基因的成年人随机分组，在研究的第1部分中，让他们每12小时口服25毫克、75毫克或150毫克的VX - 770或安慰剂，持续14天；在研究的第2部分中，让他们每12小时口服150毫克或250毫克的VX - 770或安慰剂，持续28天。
在第28天，接受150毫克VX - 770的受试者组中，鼻电位差（在给予无氯的异丙肾上腺素溶液后的反应）相对于基线的中位变化为 - 3.5毫伏（范围为 - 8.3至0.5；受试者自身比较P = 0.02，与安慰剂比较P = 0.13），汗液氯化物水平的中位变化为每升 - 59.5毫摩尔（范围为 - 66.0至 - 19.0；受试者自身比较P = 0.008，与安慰剂比较P = 0.02）。一秒用力呼气量占预计值百分比相对于基线的中位变化为8.7%（范围为2.3%至31.3%；受试者自身比较P = 0.008，与安慰剂比较P = 0.56）。没有受试者退出研究。两名受试者发生了6起严重不良事件（一名受试者出现弥漫性黄斑皮疹，一名患有糖尿病的受试者出现5次血糖和尿糖水平升高的情况）。所有严重不良事件在未停用VX - 770的情况下得到解决。
这项评估VX - 770安全性和不良事件情况的研究表明，VX - 770与受试者自身CFTR和肺功能的改善有关。这些发现为进一步研究CFTR的药物增效作为治疗囊性纤维化的一种手段提供了支持。
A new approach in the treatment of cystic fibrosis involves improving the function of mutant cystic fibrosis transmembrane conductance regulator (CFTR). VX-770, a CFTR potentiator, has been shown to increase the activity of wild-type and defective cell-surface CFTR in vitro. We randomly assigned 39 adults with cystic fibrosis and at least one G551D-CFTR allele to receive oral VX-770 every 12 hours at a dose of 25, 75, or 150 mg or placebo for 14 days (in part 1 of the study) or VX-770 every 12 hours at a dose of 150 or 250 mg or placebo for 28 days (in part 2 of the study). At day 28, in the group of subjects who received 150 mg of VX-770, the median change in the nasal potential difference (in response to the administration of a chloride-free isoproterenol solution) from baseline was −3.5 mV (range, −8.3 to 0.5; P = 0.02 for the within-subject comparison, P = 0.13 vs. placebo), and the median change in the level of sweat chloride was −59.5 mmol per liter (range, −66.0 to −19.0; P = 0.008 within-subject, P = 0.02 vs. placebo). The median change from baseline in the percent of predicted forced expiratory volume in 1 second was 8.7% (range, 2.3 to 31.3; P = 0.008 for the within-subject comparison, P = 0.56 vs. placebo). None of the subjects withdrew from the study. Six severe adverse events occurred in two subjects (diffuse macular rash in one subject and five incidents of elevated blood and urine glucose levels in one subject with diabetes). All severe adverse events resolved without the discontinuation of VX-770. This study to evaluate the safety and adverse-event profile of VX-770 showed that VX-770 was associated with within-subject improvements in CFTR and lung function. These findings provide support for further studies of pharmacologic potentiation of CFTR as a means to treat cystic fibrosis.